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CELLULAR SCIENCE


Researcher in Boston USA have summarised the current known biomarkers, including dysplasia, genomic markers, and gene expression alterations that occur early in the dysplasia/ carcinoma sequence.2


Despite the


tremendous breadth of work in studying molecular advances, the ideal biomarker for Barrett’s oesophagus has yet to be discerned. However, there are innovations in the field of Barrett’s research that combine state-of-the-art molecular advances with simple technologies.


Molecular reprogramming Barrett’s oesophagus is the condition in which metaplastic columnar epithelium that predisposes to cancer development replaces stratified squamous epithelium in the distal oesophagus. Potential sources for the cell or tissue of origin for metaplastic Barrett’s epithelium have been reviewed by researchers working in Dallas, Texas.3


They reviewed native


oesophageal differentiated squamous cells, progenitor cells native to the oesophagus located within the squamous epithelium or in the submucosal glands or ducts, circulating bone marrow-derived stem cells, and columnar progenitor cells from the squamocolumnar junction or the gastric cardia that proximally shift into the oesophagus to fill voids left by damaged squamous epithelium. Wherever its source, the original cell must undergo molecular reprogramming (ie either transdifferentiation or transcommitment) to give rise to specialised intestinal metaplasia. Transcription factors that specify squamous, columnar, intestinal and mucus-secreting epithelial differentiation were considered in order to improve the understanding of how oesophageal columnar metaplasia forms, and the development of normal tissue development and differentiation, wound healing and stem cell biology, and effective treatment or prevention strategies for Barrett’s oesophagus.


Complex, clonal and controversial Barrett’s oesophagus is a preneoplastic condition described as the replacement of the stratified squamous epithelium of the distal oesophagus with one that histologically presents as a diverse mixture of metaplastic glands resembling gastric or intestinal-type columnar


Three main subtypes of intestinal metaplasia have been recognised and there may be a strong link between type III and both oesophageal and intestinal-type gastric adenocarcinoma


epithelium. The clonal origins of Barrett’s oesophagus remain unclear and therefore researchers at Queen Mary University of London (QMUL) investigated the relationship between the various metaplastic gland phenotypes observed in Barrett’s oesophagus, how they evolve, and the cancer risk they bestow.4 Studies show that glands along the


Barrett’s oesophagus segment are clonal units containing a single stem cell clone that can give rise to all the differentiated epithelial cell types in glands. Clonal lineage tracing analysis has revealed that Barrett’s glands are capable of bifurcation and this facilitates clonal expansion and competition. In some patients, however, Barrett’s oesophagus appears to consist of multiple, independently initiated clones that compete with each other for space and possibly resources.


In addition, the QMUL study discusses the concepts of clonal competition and expansion in Barrett’s oesophagus and sets out to query what is known about the role of gland diversity and phenotypic evolution within this complex columnar metaplasia.


Toll-like receptors and transformation Toll-like receptors (TLRs) are immunological receptors recognising various microbial and endogenous ligands, such as DNA, RNA and other microbial and host components, which activate immunological responses. The expression of TLRs in oesophageal adenocarcinoma is not well known, and the aim of a study from Finland was to evaluate expression patterns of those TLRs that sense nucleic acids in Barrett’s oesophagus with and without dysplasia and in oesophageal adenocarcinoma.5 The TLRs 3, 7 and 8 were stained immunohistochemically and evaluated in a cohort of patients with oesophageal adenocarcinoma or dysplasia. Specimens with normal oesophagus (n=88), gastric (n=67) or intestinal metaplasia (n=51) without dysplasia, and low-grade (n=42)


Clonal lineage tracing analysis has revealed that Barrett’s glands are capable of bifurcation and this facilitates clonal expansion and competition


54


or high-grade dysplasia (n=37) and oesophageal adenocarcinoma (n=99) were studied.


The authors used immunofluorescence


to confirm the subcellular localisation of TLRs, and found abundant expression of TLR3, 7 and 8 in oesophageal squamous epithelium, columnar metaplasia, dysplasia and adenocarcinoma. Cytoplasmic expression of TLR3, TLR7 or TLR8 was not associated with clinicopathological parameters or prognosis in oesophageal cancer. High nuclear expression of TLR8,


confirmed with immunofluorescence, in cancer cells was observed in tumours of high T-stage (P<0.01) and in tumours with organ metastasis (P<0.001). High nuclear TLR8 expression was associated with poor prognosis (P<0.001). The expression of TLR3, TLR7 and TLR8 increased toward dysplasia and adenocarcinoma. In summary, the results demonstrated nuclear localisation of TLR8, which was associated with metastasis and poor prognosis; however, TLR3 and TLR7 did not appear to have prognostic significance in oesophageal adenocarcinoma.


References 1 Smith JL, Dixon MF. Is subtyping of


intestinal metaplasia in the upper gastrointestinal tract a worthwhile exercise? An evaluation of current mucin histochemical stains. Br J Biomed Sci 2003; 60 (4): 180–6. doi: 10.1080/ 09674845.2003.11783696.


2 Qureshi AP, Stachler MD, Haque O, Odze RD. Biomarkers for Barrett’s esophagus - a contemporary review. Expert Rev Mol Diagn 2018; 18 (11):939–46. doi: 10.1080/14737159.2018.1538793.


3 Wang DH, Souza RF. Transcommitment: paving the way to Barrett’s metaplasia. Adv Exp Med Biol 2016; 908: 183–212. doi: 10.1007/978-3-319-41388-4_10.


4 Evans JA, McDonald SA. The complex, clonal and controversial nature of Barrett’s esophagus. Adv Exp Med Biol 2016; 908: 27–40. doi: 10.1007/978-3-319-41388-4_3.


5 Helminen O, Huhta H, Lehenkari PP, Saarnio J, Karttunen TJ, Kauppila JH. Nucleic acid-sensing Toll-like receptors 3, 7 and 8 in esophageal epithelium, Barrett’s esophagus, dysplasia and adenocarcinoma. Oncoimmunology 2016; 5 (5): e1127495. doi: 10.1080/ 2162402X.2015.1127495.


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